Genetically Predicted Body Mass Index and Breast Cancer Risk: Mendelian Randomization Analyses of Data from 145,000 Women of European Descent

Journal article

Publication Details

Author(s): Guo Y, Andersen SW, Shu XO, Michailidou K, Bolla MK, Wang Q, Garcia-Closas M, Milne RL, Schmidt MK, Chang-Claude J, Dunning A, Bojesen SE, Ahsan H, Aittomaki K, Andrulis IL, Anton-Culver H, Arndt V, Beckmann M, Beeghly-Fadiel A, Benitez J, Bogdanova NV, Bonanni B, Borresen-Dale AL, Brand J, Brauch H, Brenner H, Bruening T, Burwinkel B, Casey G, Chenevix-Trench G, Couch FJ, Cox A, Cross SS, Czene K, Devilee P, Doerk T, Dumont M, Fasching P, Figueroa J, Flesch-Janys D, Fletcher O, Flyger H, Fostira F, Gammon M, Giles GG, Guenel P, Haiman CA, Hamann U, Hooning MJ, Hopper JL, Jakubowska A, Jasmine F, Jenkins M, John EM, Johnson N, Jones ME, Kabisch M, Kibriya M, Knight JA, Koppert LB, Kosma VM, Kristensen V, Le Marchand L, Lee E, Li J, Lindblom A, Luben R, Lubinski J, Malone KE, Mannermaa A, Margolin S, Marme F, Mclean C, Meijers-Heijboer H, Meindl A, Neuhausen SL, Nevanlinna H, Neven P, Olson JE, Perez JIA, Perkins B, Peterlongo P, Phillips KA, Pylkas K, Rudolph A, Santella R, Sawyer EJ, Schmutzler RK, Seynaeve C, Shah M, Shrubsole MJ, Southey MC, Swerdlow AJ, Toland AE, Tomlinson I, Torres D, Truong T, Ursin G, Van Der Luijt RB, Verhoef S, Whittemore AS, Winqvist R, Zhao H, Zhao S, Hall P, Simard J, Kraft P, Pharoah P, Hunter D, Easton DF, Zheng W
Journal: Plos Medicine
Publication year: 2016
Volume: 13
Journal issue: 8
ISSN: 1549-1277
eISSN: 1549-1676


BACKGROUND: Observational epidemiological studies have shown that high body mass index (BMI) is associated with a reduced risk of breast cancer in premenopausal women but an increased risk in postmenopausal women. It is unclear whether this association is mediated through shared genetic or environmental factors.
METHODS: We applied Mendelian randomization to evaluate the association between BMI and risk of breast cancer occurrence using data from two large breast cancer consortia. We created a weighted BMI genetic score comprising 84 BMI-associated genetic variants to predicted BMI. We evaluated genetically predicted BMI in association with breast cancer risk using individual-level data from the Breast Cancer Association Consortium (BCAC) (cases  =  46,325, controls  =  42,482). We further evaluated the association between genetically predicted BMI and breast cancer risk using summary statistics from 16,003 cases and 41,335 controls from the Discovery, Biology, and Risk of Inherited Variants in Breast Cancer (DRIVE) Project. Because most studies measured BMI after cancer diagnosis, we could not conduct a parallel analysis to adequately evaluate the association of measured BMI with breast cancer risk prospectively.
RESULTS: In the BCAC data, genetically predicted BMI was found to be inversely associated with breast cancer risk (odds ratio [OR]  =  0.65 per 5 kg/m2 increase, 95% confidence interval [CI]: 0.56-0.75, p = 3.32 × 10-10). The associations were similar for both premenopausal (OR   =   0.44, 95% CI:0.31-0.62, p  =  9.91 × 10-8) and postmenopausal breast cancer (OR  =  0.57, 95% CI: 0.46-0.71, p  =  1.88 × 10-8). This association was replicated in the data from the DRIVE consortium (OR  =  0.72, 95% CI: 0.60-0.84, p   =   1.64 × 10-7). Single marker analyses identified 17 of the 84 BMI-associated single nucleotide polymorphisms (SNPs) in association with breast cancer risk at p < 0.05; for 16 of them, the allele associated with elevated BMI was associated with reduced breast cancer risk.
CONCLUSIONS: BMI predicted by genome-wide association studies (GWAS)-identified variants is inversely associated with the risk of both pre- and postmenopausal breast cancer. The reduced risk of postmenopausal breast cancer associated with genetically predicted BMI observed in this study differs from the positive association reported from studies using measured adult BMI. Understanding the reasons for this discrepancy may reveal insights into the complex relationship of genetic determinants of body weight in the etiology of breast cancer.

FAU Authors / FAU Editors

Beckmann, Matthias Prof. Dr.
Lehrstuhl für Geburtshilfe und Frauenheilkunde
Fasching, Peter PD Dr.
Professur für Translationale Frauenheilkunde und Geburtshilfe

External institutions with authors

Antoni van Leeuwenhoek
Beckman Research Institute of City of Hope (BRI)
Cancer Council Victoria
Cancer Prevention Institute of California (CPIC)
Center for Cancer Biology (CCB) (formerly Vesalius Research Center (VRC))
Columbia University
Copenhagen University Hospital
Deutsches Krebsforschungszentrum (DKFZ)
Erasmus University Rotterdam (EUR) / Erasmus Universiteit Rotterdam
European Institute of Oncology / Istituto Europeo di Oncologia (IEO)
Fred Hutchinson Cancer Research Center
Hannover Medical School / Medizinische Hochschule Hannover (MHH)
Harvard University
Helsingin yliopisto / University of Helsinki
Hospital Monte Naranco
IFOM - FIRC Institute of Molecular Oncology
Karolinska Institute
King’s College London
Kuopio University Hospital / Pohjois-Savon sairaanhoitopiiri
Leiden University
Mayo Clinic
Mount Sinai Hospital (MSH)
National Cancer Institute (NCI)
National Centre for Scientific Research (NCSR) "Demokritos"
National Institute for Health and Medical Research / Institut national de la santé et de la recherche médicale (INSERM)
Ohio State University
Oslo University Hospital / Oslo Universitetssykehus
Oulun Yliopisto / University of Oulo
Pomeranian Medical University / Pomorski Uniwersytet Medyczny w Szczecinie (PMU)
QIMR Berghofer Medical Research Institute (früher: the Queensland Institute of Medical Research)
Ruhr-Universität Bochum (RUB)
Ruprecht-Karls-Universität Heidelberg
Spanish National Cancer Research Centre / Centro Nacional de Investigaciones Oncológicas (CNIO)
Stanford University
Technische Universität München (TUM)
The Alfred Hospital
The Institute of Cancer Research (ICR)
The University of Melbourne
Universitätsklinikum Hamburg-Eppendorf (UKE)
Universitätsklinikum Köln
Université Laval (UL)
University Hospital Leuven (UZ) / Universitaire ziekenhuizen Leuven
University Medical Centre Utrecht (UMC Utrecht)
University of California Irvine
University of Cambridge
University of Chicago
University of Copenhagen
University of Hawaii (U.H.)
University of North Carolina at Chapel Hill
University of Oxford
University of Sheffield
University of Southern California (USC)
Vanderbilt University
Vrije Universiteit Amsterdam (VU) / University Amsterdam

How to cite

Guo, Y., Andersen, S.W., Shu, X.-O., Michailidou, K., Bolla, M.K., Wang, Q.,... Zheng, W. (2016). Genetically Predicted Body Mass Index and Breast Cancer Risk: Mendelian Randomization Analyses of Data from 145,000 Women of European Descent. Plos Medicine, 13(8).

Guo, Yan, et al. "Genetically Predicted Body Mass Index and Breast Cancer Risk: Mendelian Randomization Analyses of Data from 145,000 Women of European Descent." Plos Medicine 13.8 (2016).


Last updated on 2019-21-07 at 08:01